Meningioma, Familial, Susceptibility To

A number sign (#) is used with this entry because susceptibility to the development of meningioma is caused by heterozygous mutation in the SMARCE1 gene (603111) on chromosome 17q21.

Heterozygous germline mutations in the SUFU gene (607035) on chromosome 10q24 and in the PDGFB gene (190040) on chromosome 22q, respectively, have been reported in 1 family with meningioma.

Somatic mutations in the gene encoding merlin (NF2; 607379) on chromosome 22q12 have also been found in tumor tissues of a subset of patients with meningiomas without other features of neurofibromatosis-2 (101000).

Description

Meningiomas are, in general, slowly growing benign tumors derived from the arachnoidal cap cells of the leptomeninges, the soft coverings of the brain and spinal cord. Meningiomas are believed to be the most common primary tumors of the central nervous system in man. The vast majority of meningiomas are sporadic; familial occurrence of meningioma is rare (Zang, 2001).

Familial or multiple meningiomas may also be seen in tumor predisposition syndromes. Some patients with schwannomatosis (162091), caused by mutation in the SMARCB1 gene, may develop meningiomas. One patient with malignant gliomas (GLM2; 613028) associated with a mutation in the PTEN gene (601728) developed a meningioma (Staal et al., 2002).

Clinical Features

Aavikko et al. (2012) reported a Finnish family in which 5 sibs had adult-onset meningiomas between the ages of 43 and 72 years. Four of the 5 had multiple tumors. Germline and somatic alterations of the NF2 gene were excluded in these patients. No mutation carriers had medulloblastoma.

Smith et al. (2013) reported 6 patients from 4 unrelated families with spinal meningiomas. The age at onset was between 15 and 30 years, and 5 of the patients were female. Three of the woman developed the tumors during pregnancy, suggesting a hormonal influence on penetrance. All tumors showed a clear-cell histology.

Inheritance

Sedzimir et al. (1973) reported monozygotic twins with meningioma. Memon (1980) reported a 63-year-old woman with multiple meningiomas who had a son with a histologically similar tumor, and Pamphlett and Mackenzie (1981) reported a father and daughter with meningioma.

Yamanaka et al. (1984) reported 2 families in which 1 sib had meningioma and a second sib had schwannoma. Bolger et al. (1985) described a family in which a father and 3 of his 8 children had meningioma with clinical onset at ages ranging from 35 to 65 years. A fourth offspring died of multiple neoplasms arising at age 29 years. Ferrante et al. (1987) reported 2 sisters and McDowell (1990) reported a mother and 3 daughters with the disease. Sieb et al. (1992) described a family with 4 individuals in 2 generations with meningioma, and suggested autosomal dominant inheritance with high penetrance. Maxwell et al. (1998) found only 14 reports (since 1959) of familial meningioma in isolation from NF2. They reported a family lacking any stigmata of NF2 in which the mother and a daughter and son had meningiomas. In the 2 offspring, the meningiomas were spinal. Also see Joynt and Perret (1961).

The transmission pattern of meningioma in the family reported by Aavikko et al. (2012) was consistent with autosomal dominant inheritance.

Association with Neurofibromatosis Type II

Patients with neurofibromatosis type II (NF2; 101000) are predisposed to a variety of central nervous system tumors, including vestibular schwannomas and meningiomas. Accordingly, multiple and familial occurrences of meningiomas have usually been reported in cases of NF2 (Cogen et al., 1991; MacCollin, 1999).

Delleman et al. (1978) observed meningioma in 5 members of 2 generations, with male-to-male transmission. One of the 5 had schwannoma, or acoustic neuroma. A member of the second generation, not available for examination, was said to have multiple cafe-au-lait spots. The authors viewed the kindred as one of neurofibromatosis with wide variability.

Maxwell et al. (1998) stated that almost all cases of familial meningioma occur in association with NF2.

Cytogenetics

Bolger et al. (1985) found that 3 sibs with meningioma carried a constitutional Robertsonian 14;22 translocation, t(14;22)(14qter-cen;22qter), in circulating leukocytes. Three additional sibs from the same family without meningioma had a normal karyotype. However, in the next generation, 4 carriers of the translocation were asymptomatic, except for one with breast cancer.

Arinami et al. (1986) described an institutionalized mentally retarded male with a constitutional ring chromosome 22 discovered during a cytogenetic survey. There appeared to be deletion of 22q13.3-qter. He died at age 27 and was found to have meningeal hypoplasia and dysplasia, including meningiomatosis and an unusual cyst containing meningocytic elements. Pressure of the cyst on the brainstem was thought to have caused death. Petrella et al. (1993) described a patient with multiple congenital anomalies and ring chromosome 22 who died at age 16 years of bronchopneumonia and was found at autopsy to have multiple psammomatous meningiomas of the spinal dura and tentorium. They stated that this was only the third report of a constitutional chromosome 22 abnormality associated with the development of meningiomas and suggested that patients with the chromosomal abnormality may be predisposed to the development of meningiomas. However, they also noted that in a previous study of 21 patients with ring chromosome 22 (Hunter et al., 1977), none was reported to have meningiomas.

Somatic Cytogenetic Abnormalities

The tumor tissue of sporadic meningiomas often shows absence of one chromosome 22 or, less frequently, absence of distal 22q (Zang and Singer, 1967; Sandberg, 1980; Zang, 1982).

Casalone et al. (1987) confirmed the high frequency of abnormalities involving chromosome 22 in studies of 31 cases of meningiomas. They suggested that bands 22q11-q12 are critical. Seizinger et al. (1987) contributed to the evidence that chromosome 22 is involved in meningioma. In 17 of 40 constitutionally heterozygous patients (43%), hemizygosity for the corresponding DNA marker was found in their tumors. Meese et al. (1987) did similar studies; 3 of 12 patients showed loss of heterozygosity (LOH) of markers on chromosome 22. Using DNA markers, Okazaki et al. (1988) found loss of constitutional heterozygosity in 3 of 11 informative cases of meningioma. Maltby et al. (1988) studied the chromosomes from 50 meningiomas. Twenty-three of these tissue specimens had a normal diploid karyotype. Twenty-five had monosomy for chromosome 22, with or without a normal diploid line and/or additional aneuploidy. Cell lines monosomic for chromosome 22 also frequently had random chromosome loss. Lekanne Deprez et al. (1995) found partial or complete loss of chromosome 22 in 66 of 93 meningiomas.

Dumanski et al. (1987) studied LOH for chromosome 22 loci in tumor and normal tissue from 35 unrelated patients. Sixteen tumors retained the constitutional genotype along chromosome 22, while 14 tumors (40%) showed loss of 1 constitutional allele at all informative loci, consistent with monosomy 22 in the tumor DNA. The remaining 5 tumors (14%) showed LOH in the tumor DNA at 1 or more chromosome 22 loci and retained heterozygosity at other loci, consistent with other variable terminal deletions of 1 chromosome 22 in the tumor DNA. The results in these cases suggested that a meningioma locus is located distal to the myoglobin locus, within 22q12.3-qter. Multiple loci on other chromosomes also were studied, and 12 of the 19 tumors with losses of chromosome 22 alleles showed additional losses of heterozygosity at loci on 1 to 3 other chromosomes. All tumors that retained the constitutional genotype on chromosome 22 also retained heterozygosity on all informative loci on other chromosomes analyzed, suggesting that the rearrangement of chromosome 22 was the primary event in the tumorigenesis of meningioma. In a larger series that incorporated the earlier one, Dumanski et al. (1990) compared constitutional and tumor tissue genotypes from 81 unrelated patients with meningioma, studying 25 polymorphic loci on chromosome 22. In 30 tumors (37%) constitutional genotype was retained, consistent with no detectable aberrations on chromosome 22. In 42 tumors (52%) there was loss of 1 allele at all informative loci, consistent with monosomy 22 in the tumor DNA. The remaining 9 tumors (11%) retained constitutional heterozygosity in the tumor DNA at 1 or more centromeric loci and showed a loss of heterozygosity at other telomeric loci, consistent with variable terminal deletions of 1 chromosome 22q in the tumor DNA.

Fontaine et al. (1990) found that LOH in sporadic meningiomas involved the maternally derived chromosome 22 in 5 tumors and the paternally derived chromosome 22 in 4. Thus, in contrast to embryonal tumors (retinoblastoma and Wilms tumor), imprinting is apparently not a factor. Sanson et al. (1990) also found both maternal and paternal origin of the lost chromosome 22 in meningioma.

Zang (2001) karyotyped 394 meningiomas and reported the significant findings: 177 were diploid, 115 showed monosomy 22, 35 had monosomy 22 and loss of 1 to 5 additional chromosomes (-14, -18, -19, -10, -6), 49 had loss of 1p in addition to loss of 22 and other chromosomal loss, and 9 had only loss of 1p. The authors noted that increasing hypodiploidy was correlated with atypical or anaplastic tumor histology and that loss of 1p was associated with a more aggressive biologic course. Zang (2001) proposed several schemata of stepwise mechanisms in the development and progression of meningiomas. Noting a correlation between losses in 1p and reductions in the amount and activity of alkaline phosphatase (ALPL; 171760), Zang (2001) suggested that ALPL may be the involved gene on chromosome 1.

Mapping

By studies of tumor tissue, Dumanski et al. (1987, 1990) concluded that a meningioma locus is located distal to the myoglobin locus, within 22q12.3-qter. Dumanski et al. (1990) concluded that the meningioma locus is distinct from the NF2 locus (607174) inasmuch as they appear to be on opposite sides of the DNA marker D22S28.

Chung and Seizinger (1992) stated that although similar deletions of chromosome 22 have been found in acoustic neuroma and meningioma, it remained unclear whether distinct genetic loci were involved.

Pulst et al. (1992, 1993) presented linkage data suggesting that a meningioma locus is separate from the NF2 locus. They described multiple meningiomas and ependymomas in 2 generations of a family. Multipoint linkage analysis resulted in location scores less than -2 for a region of 15 cM, including the NF2 region.

By screening 8 of the 16 known NF2 exons in 151 sporadic meningiomas, Ruttledge et al. (1994) identified 24 inactivating mutations in the NF2 gene. Significantly, these aberrations were exclusively detected in tumors that lost the other chromosome 22 allele, suggesting that the suppressor gene on chromosome 22 is the NF2 gene. However, Ruttledge et al. (1994) suggested that another gene is involved in the development of about 40% of meningiomas. The same group found that 95% of fibroblastic meningiomas showed LOH on chromosome 22, whereas only one-third of tumors classified as meningothelial showed LOH on this autosome. Thus, variation in meningioma histology may reflect mutations at separate genetic loci. Tumors of purely fibroblastic histology may represent a genetic subgroup in which mutation of NF2 is a factor necessary for tumorigenesis.

In 2 affected offspring of an affected mother reported by Maxwell et al. (1998), immunocytochemical analysis for the NF2 protein product merlin showed that merlin was present in the tumor specimens from 2 affected offspring from an affected mother, implying that the NF2 tumor suppressor gene was not deleted in these tumors. The findings suggested that a second tumor suppressor gene locus, other than NF2, acts in the formation of familial 'sporadic' meningioma.

Zang (2001) suggested 'combined heterozygous loss' of NF2 and a second meningioma locus on chromosome 22 to explain the tumor suppressor gene mechanism.

Molecular Genetics

Mutation in the SUFU Gene

In affected members of a Finnish family with multiple adult-onset meningiomas, Aavikko et al. (2012) identified a germline heterozygous mutation in the SUFU gene (R123C; 607035.0007). The mutation was identified by genomewide linkage analysis combined with exome sequencing. Tumor tissue from 7 meningiomas showed loss of heterozygosity at the SUFU locus, consistent with a 2-hit model for tumor suppressor genes. In vitro functional expression studies in human rhabdomyosarcoma cells showed that the R123C mutant protein had a significantly decreased ability to suppress GLI1 (165220) activity compared to wildtype SUFU, resulting in aberrant activation of the hedgehog signaling pathway. SUFU mutations were not identified in 162 additional Finnish patients with meningioma.

PDGFB Gene

Bolger et al. (1985) reported 2 living sibs with meningioma who were found to have a variant of the SIS oncogene (PDGFB; 190040) on chromosome 22q12 in peripheral leukocyte DNA. Family studies showed that the SIS variant segregated with the normal chromosome 22. Later studies by Smidt et al. (1990) showed that the affected members of the family reported by Bolger et al. (1985) had deletion of Alu sequences in the fifth intron of the SIS gene (190040.0001).

MN1 Disruption

Lekanne Deprez et al. (1995) used a balanced translocation involving chromosome 22 from a meningioma to isolate a gene they designated MN1 (156100) which was disrupted by the translocation. In the meningioma carrying this translocation, no expression of the MN1 mRNA was observed. The translocation in this case represented a germline change in a patient with multiple meningiomas (Lekanne Deprez et al., 1991).

SMARCB1 Gene

Bacci et al. (2010) reported a family in which affected individuals had multiple schwannomas and meningiomas associated with a heterozygous mutation in the SMARCB1 gene (E31V; 601607.0010). Bacci et al. (2010) noted that meningiomas are not frequently found in patients with schwannomatosis (162091), but should be considered part of the phenotype.

Christiaans et al. (2011) reported a family in which 5 individuals developed meningiomas, 2 of whom also developed schwannomas. All patients carried a heterozygous mutation in the SMARCB1 gene (P48L; 601607.0011), and meningioma tumors showed loss of the wildtype allele, consistent with the 2-hit hypothesis of tumorigenesis. Meningiomas developed between ages 34 and 56 years, both in the cranium as extra-axial lesions and in the spinal cord as extramedullary lesions. In addition, 1 patient developed multiple chest wall and spinal schwannomas and another developed a single vestibular schwannoma. Two different meningioma tumors from the same patient also carried 2 different heterozygous somatic mutations in the NF2 gene (607379) as well as loss of heterozygosity at the NF2 locus. Christiaans et al. (2011) concluded that the SMARCB1 mutation predisposed the carriers to the development of meningiomas. The mutation may also have predisposed carriers to schwannomas, implying that meningiomas may be part of the schwannomatosis tumor spectrum, as suggested by Bacci et al. (2010), but the schwannomas may also be coincidental findings. The role of the NF2 mutations was uncertain, but may contribute to a 4-hit hypothesis involving 2 genes. Van den Munckhof et al. (2012) provided further studies of the family reported by Christiaans et al. (2011). Reexamination of tumor tissue from 4 meningiomas and 2 schwannomas showed that all tumors had LOH for both SMARCB1 and NF2, consistent with a deletion of a segment of chromosome 22 containing these 2 genes. Three meningiomas and 2 schwannomas were each found to carry somatic mutations in the NF2 gene. Thus, the genetic changes found in the 2 tumor types were the same and characteristic for SMARCB1-mutation positive tumors: retention of the exon 2 mutation, acquisition of an NF2 mutation, and LOH of the wildtype allele of both genes. In addition, van den Munckhof et al. (2012) identified 11 more carriers of the P48L mutation in this family. Eight of these 11 mutation carriers were found to carry 11 lesions suggestive of cranial meningioma and 6 spinal lesions consistent with meningiomas or schwannomas. Nine (82%) of the 11 cranial meningiomas were found in the falx cerebri. Van den Munckhof et al. (2012) concluded that meningiomas should be included in the schwannomatosis tumor spectrum.

SMARCE1 Gene

In 6 patients from 4 unrelated families with spinal meningiomas, Smith et al. (2013) identified 4 different heterozygous loss-of-function mutations in the SMARCE1 gene (603111.0002-603111.0005). The first 2 mutations were identified by exome sequencing, and the second 2 were found by Sanger sequencing of the SMARCE1 gene in 6 additional patients with spinal meningiomas. One unaffected father was heterozygous for the mutation, indicating incomplete penetrance. All spinal tumors were clear-cell type, and all tumors studied showed loss of the SMARCE1 protein, consistent with a tumor suppressor mechanism. However, only 1 of 3 tumors analyzed showed loss of heterozygosity for wildtype SMARCE1. Sequencing SMARCE1 in 34 individuals with multiple cranial meningiomas did not identify any mutations, suggesting that the mutations are specific for spinal tumors. Smith et al. (2013) postulated that loss of SMARCE1 activity may lead to the uncoupling of apoptotic control.

Associations Pending Confirmation

Dobbins et al. (2011) performed a genomewide association study of 859 affected individuals with meningioma and 704 controls with validation in 2 independent sample sets totaling 774 cases and 1,764 controls. They identified a new susceptibility locus for meningioma at 10p12.31 in the MLLT10 gene (602409) at rs11012732 (odds ratio = 1.46, combined P value = 1.88 x 10(-14)).

Somatic Mutations

In 8 of 70 sporadic meningiomas, Peyrard et al. (1994) found specific loss of expression of a beta-adaptin gene called BAM22 (600157). They reviewed the evidence suggesting that multiple genes on chromosome 22 are involved in the oncogenesis of meningioma and suggested that BAM22 may be second in importance to the NF2 (607379) gene.

Wellenreuther et al. (1995) suggested that the NF2 gene represents the meningioma locus on chromosome 22. The association of LOH on chromosome 22 with somatic mutations in the NF2 gene was significant. Somatic NF2 mutations occurred significantly more frequently in fibroblastic meningioma (70%) and transitional meningioma (83%) than in meningiothelial meningioma (25%), thus indicating a differential molecular pathogenesis of these meningioma variants.

Schmitz et al. (2001) found the same somatic mutation (R377H) in exon 9 of the SMARCB1 gene in 4 of 126 meningiomas. The data indicated that SMARCB1 is a candidate tumor suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.

Eckstein et al. (2004) reported a 42-year-old man with a single meningioma that was resected. Over the next 15 years, he developed multiple recurrent meningiomas with the same histopathology in different areas of the brain, spinal cord, and lung. He had no clinical history of NF2 or vestibular schwannomas and no family history of meningioma. Genetic analysis of all tumor DNA identified a somatic 2-bp deletion in exon 1 of the NF2 gene, which was not present in the patient's blood. The second NF2 allele was lost in the tumors, consistent with the action of NF2 as a tumor suppressor gene. Eckstein et al. (2004) noted the unusual recurrence, long survival, and lack of histologic progression of the tumor over a long period of time and postulated that other genes may be involved.

Brastianos et al. (2013) performed whole-genome or whole-exome sequencing on 17 meningiomas and sequenced an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements, and copy number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy number changes and rearrangements, including 1 tumor with chromothripsis. Brastianos et al. (2013) confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (164730) (E17K) and SMO (601500) (W535L) and exhibited immunohistochemical evidence of activation of these pathways.